The present invention relates to a parenteral composition comprising a bisphosphonic acid or a pharmaceutically acceptable salt thereof (bisphosphonate) as active component, a pharmaceutically acceptable chelating agent and pharmaceutically acceptable excipients, processes of the preparation of this composition, and methods of their use in the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget""s disease, hypercalcemia of malignancy, and metabolic bone disease. The compositions are especially useful for improving the local tolerance of the active component when administered parenterally, especially by the subcutaneous route.
Bisphosphonates, i.e. bisphosphonic acids or soluble, pharmaceutically acceptable salts thereof, are synthetic analogs of the naturally occurring pyrophosphate. Due to their marked affinity for solid-phase calcium phosphate, bisphosphonates bind strongly to bone mineral. Pharmacologically active bisphosphonates are well known in the art and are potent inhibitors of bone resorption and are therefore useful in the treatment and prevention of diseases involving abnormal bone resorption, especially osteoporosis, Paget""s disease, hypercalcemia of malignancy, and metabolic bone disease.
Bisphosphonates as pharmaceutical agents are described for example in EP-A-170,228, EP-A-197,478, EP-A-22,751; EP-A-252,504, EP-A-252,505, EP-A-258,618, EP-A-350,002, EP-A-273,190, WO-A-90/00798, etc.
Pharmaceutical forms of marketed bisphosphonates are oral formulations (tablets or capsules) or solutions for intravenous injection or infusion. They are systemically well tolerated when administered at therapeutic doses. However, bisphosphonates as a class are irritant to skin and mucous membranes resulting in digestive tract side effects, e.g. esophageal adverse events or gastrointestinal disturbances. In consequence, the oral route of administration has to follow inconvenient recommendations of use for the patient. The intravenous route of administration is complicated by adverse events in case of application failure. If the vein is not exactly met or if the drug is administered inadvertently by the paravenous route, severe local tissue reaction are induced including necroses. Thus, there is a substantial need to improve the pharmaceutical formulation of bisphosphonates in order to reduce or avoid tissue damage after parenteral administration, especially by the subcutaneous route.
The pathophysiological mechanism of bisphosphonate induced tissue damage is unknown. As the local reactions are similar for different bisphosphonates, at least those induced by nitrogen-containing bisphosphonates (amino-bisphosphonates), a common mechanism must be assumed. The delay in onset and progress of local reactions may indicate the involvement of the unspecific immune defense system.
Attempts were made to improve tissue tolerance of bisphosphonates by developing suspensions of insoluble or poorly soluble salts of bisphosphonates providing local sustained release, e.g. described in EP 449,405, DE-A-4244422 and DE-A-4244423. However, this approach proved to improve only slightly the local tolerance.
The problem underlying the present invention is therefore to provide a composition which is able to minimize or suppress the above mentioned disadvantages.
The problem is solved, according to the present invention, by a parenteral composition comprising a bisphosphonate and a pharmaceutically acceptable chelating agent.
It has surprisingly been found that administering a bisphosphonate in a composition comprising a pharmaceutically acceptable chelating agent clearly improves the duration, frequency and intensity of side effects. The presence of an additional bivalent cation chelator, especially EDTA and DTPA, substantially improved the adverse local reaction at the application sites when compared with the corresponding formulation without this additional bivalent cation chelator. A pharmaceutically acceptable excipient may also be added to the composition.